AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients (NAViRe)

• ClinicalTrials.gov Identifier: NCT04690933
• Recruitment Status: Recruiting
• First Posted: December 31, 2020
• Last Update Posted: December 31, 2020
• Sponsor: University Hospital, Limoges
• Information provided by (Responsible Party): University Hospital, Limoges

Tracking Information

• First Submitted Date: September 14, 2020
• First Posted Date: December 31, 2020
• Last Update Posted Date: December 31, 2020
• Actual Study Start Date: September 24, 2020
• Estimated Primary Completion Date: September 24, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 30, 2020)

• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: between Day-30 and Day -8 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: between Day-8 and Day 0 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: at Day20 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: at Day100 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: at Day 200 (Month 6) ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: Month12 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen
• CMV infection according to criteria defined by the European EBMT group (Ljungman et al., 2017). [ Time Frame: Month24 ]
  CMV detection (CMV DNAemia or antigen detection) in any body fluid or tissue specimen

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: December 30, 2020)

• Uses of anti-CMV molecules : preemptive treatment [ Time Frame: at Day200 ]
  % of patients having received preemptive treatment
• Uses of anti-CMV molecules : prophylaxis [ Time Frame: at Day200 ]
  % of patients having received prophylaxis
• Uses of anti-CMV molecules : curative treatment [ Time Frame: at Day200 ]
  % of patients having received curative treatment
• Uses of anti-CMV molecules [ Time Frame: at Day200 ]
  Cumulative duration of exposure (number of day) for each drug administered
• Uses of anti-CMV molecules : preemptive treatment [ Time Frame: at Month12 ]
  % of patients having received preemptive treatment
• Uses of anti-CMV molecules : prophylaxis [ Time Frame: at Month12 ]
  % of patients having received prophylaxis
• Uses of anti-CMV molecules : curative treatment [ Time Frame: at Month12 ]
  % of patients having received curative treatment
• Uses of anti-CMV molecules [ Time Frame: at Month12 ]
  Cumulative duration of exposure (number of day) for each drug administered
• Uses of anti-CMV molecules : preemptive treatment [ Time Frame: at Month24 ]
  % of patients having received preemptive treatment
• Uses of anti-CMV molecules : prophylaxis [ Time Frame: at Month24 ]
  % of patients having received prophylaxis
• Uses of anti-CMV molecules : curative treatment [ Time Frame: at Month24 ]
  % of patients having received curative treatment
• Uses of anti-CMV molecules [ Time Frame: at Month24 ]
  Cumulative duration of exposure (number of day) for each drug administered
• Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in [ Time Frame: at Month12 ]
  Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in :

  • Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.
  • Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.
  • Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.
  • Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.
  • Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs.

  Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.
• Incidence of the non-response and resistance to antivirals with risk factors associated (virological, pharmacological, immunological). Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in [ Time Frame: at Month24 ]
  Criteria recently published by Chemaly et al. CID 2018 will be used to classify cases in :

  • Refractory CMV infection CMV viremia that increases after at least 2 wk of appropriately dosed antiviral therapy.
  • Probable refractory CMV infection : persistent viral load after at least 2 wk of appropriately dosed antiviral therapy.
  • Refractory CMV end organ disease : worsening in signs and symptoms or progression into end-organ disease after at least 2 wk of appropriately dosed antiviral therapy.
  • Probable refractory CMV end-organ disease : lack of improvement in signs and symptoms after at least 2 wk of appropriately dosed antiviral drugs.
  • Antiviral drug resistance : viral genetic alteration that decreases susceptibility to one or more antiviral drugs.

  Resistance : presence of a resistance-related mutation by resistance genotyping of UL97, UL54, UL56, UL89, UL27 genes, carried out or validated by the Limoges Herpesviruses reference laboratory. In blood or any other sample.
• Adverse effects leading to interruption of treatment [ Time Frame: at Month12 ]
  Incidence of treatment emergent adverse event as assessed by interruption of treatment
• Adverse effects leading to interruption of treatment [ Time Frame: at Month24 ]
  Incidence of treatment emergent adverse event as assessed by interruption of treatment
• CMV related mortality [ Time Frame: at Month12 ]
  Number of patients who died from CMV related desease
• CMV related mortality [ Time Frame: at Month24 ]
  Number of patients who died from CMV related desease
• CMV associated morbidity : delay engraftment [ Time Frame: at Month12 ]
  number of days bettwen graft and engraftment
• CMV associated morbidity : GVHD [ Time Frame: at Month12 ]
  Incidence of GVHD
• CMV associated morbidity : CMV infection/disease [ Time Frame: at Month12 ]
  Incidence of CMV infection/disease (infection or disease will be combined to report this outcome). CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms. CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).
• CMV associated morbidity : delay engraftment [ Time Frame: at Month24 ]
  number of days bettwen graft and engraftment
• CMV associated morbidity : GVHD [ Time Frame: at Month24 ]
  Incidence of GVHD
• CMV associated morbidity : CMV infection/disease [ Time Frame: at Month24 ]
  Incidence of CMV infection/disease (infection or disease will be combined to report this outcome). CMV infection : positive diagnostic test (CMV culture, antigen detection or CMV PCR), in any body fluid or tissue, in the absence of symptoms. CMV disease : CMV infection associated with end-organ disease (clinical signs and oriented virological diagnosis).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AntiCMV molécules Monitoring in Real-life in Stem Cell Recipients
• Official Title: Real-life Observatory of Efficacy and Resistance to Anti CMV Molecules in Stem Cell Recipients

Brief Summary

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

Detailed Description

Cytomegalovirus (CMV) is a ubiquitous herpesvirus that represent a major cause of morbidity in haematopoietic stem cell transplants (HSCT) recipients, mostly through reactivation of the recipient's virus.

If left untreated, 40 to 80% of patients will develop CMV infection, leading to CMV disease in 30 to 35 % patients, and associated with considerable morbi-mortality. Interstitial pneumonia is the most severe and specific manifestation, although CMV replication by itself has also indirect effects such as triggering graft versus host disease and increasing immunosuppression. The current burden of CMV infection increases by 25 to 30% the cost of the graft in France. This also includes the burden for refractory - infections, that represent up to 13% of recipients with CMV infection, including 3% of cases with virological resistance in France (data from the Reference Center cohorts).

Ganciclovir, or valganciclovir preemptive treatment, guided by CMV viral load follow-up allowed significant reduction of CMV disease to 2-6% but did not prevent CMV indirect effects. In addition, hematotoxicity can compromise post-transplant haematological reconstitution, thus preventing its use as prophylaxis in France. Foscarnet, iv-administered and nephrotoxic, remains less used. There is thus a high expectation from less toxic molecules for prophylaxis The development letermovir recently available for prophylaxis of CMV infection in high risk patients will modify the patients care and follow-up. This new molecule targeting CMV terminases (developed by Merck) was recently marketed in France (Jan 2020). However, the analysis of the letermovir phase III study and further publications show that the risk of emergence of resistance is low, but may occur in case of breakthrough and thus post AMM monitoring is required.

A "real-life" evaluation of these new molecules in terms of efficacy, emergence of resistance, tolerance and morbimortality related to CMV infection, is useful, to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients. To this purpose, the National Reference Center in collaboration with the French Society for marrow graft and cell therapy (SFGMTC) set up a cohort of surveillance of allografted patients, receiving, in prevention or treatment, old and new molecules.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Samples related to the cohort :

One blood sample from the donor (only familial donors) for genetic SNPs analysis.

5 samples: D-8 (conditioning), D20, D100 (+/- 10 days), D200 (+/- 10 days), 1 year : 1 tube of 7ml of whole blood on EDTA: Biobanking of whole blood for genetic SNPs analysis (D-8) of specific transporters for GCV, and of plasma for TTV viral load at all times. Conservation of viral load monitoring remnants at the center's virology laboratory.

• Sampling Method: Probability Sample
• Study Population: Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.

Condition

• Hematopoietic Stem Cell Transplantation
• Cytomegalovirus Infections
• Antivirals
• Antiviral Drug Resistance

Intervention

Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients

Signing of consent at the time of the pre-transplant consultation (1 month before grafting). Inclusion of patients during conditioning (around D-8 of transplantation). Samples related to the cohort:one blood sample from the donor (only familial donors) for genetic SNPs analysis. 5 samples: D-8, D20, D100, D200 (+/-10 days), 1 year : 1 tube of 7ml of whole blood on EDTA: Biobanking of whole blood for genetic SNPs analysis (D-8) of specific transporters for GCV, and of plasma for TTV viral load at all times. In routine care:samples taken in the event of a therapeutic escape (2 x 7 ml EDTA tubes, for resistance genotype, and ganciclovir dosage, 3 x 1 ml for Quantiferon CMV, according to CNR Herpesvirus recommendations. 1 x Paxgene tube (2.5 ml) for subsequent CMV genomic and transcriptomic studies. Cell preservation plasma and whole blood for biocollection (2 tubes EDTA de 7ml). Samples stored by the centers' virology laboratories are periodically sent to the CNR for analysis.

Study Groups/Cohorts

Multicentric NAViRe cohort with biocollection

The National Reference Center (CNR) for cytomegalovirus with the French Society for Medullary Transplantation and Cell Therapy (SFGM-TC) has set up a surveillance cohort of allografted patients (NAViRe cohort) receiving, as prevention or treatment, Anti-Cytomegalovirus (Anti-CMV) molecules, "new or less recent", thus allowing the development of a new observatory evaluating in real life the potentials of these drugs in terms of efficacy, emergence of resistance, tolerance and morbidity and mortality associated with CMV infection.This work is useful to propose recommendations on management strategies, in particular for the most at-risk patients i.e. CMV-seropositive recipients and allows the emergence of an real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients.

Intervention: Other: Real-life observatory of efficacy and resistance to anti CMV molecules in stem cell recipients

Publications *

• Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28.
• Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, Mullane KM, Kotton C, Lundgren J, Komatsu TE, Lischka P, Josephson F, Douglas CM, Umeh O, Miller V, Ljungman P; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019 Apr 8;68(8):1420-1426. doi: 10.1093/cid/ciy696.
• Billat PA, Ossman T, Saint-Marcoux F, Essig M, Rerolle JP, Kamar N, Rostaing L, Kaminski H, Fabre G, Otyepka M, Woillard JB, Marquet P, Trouillas P, Picard N. Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients. Pharmacol Res. 2016 Sep;111:501-508. doi: 10.1016/j.phrs.2016.07.012. Epub 2016 Jul 9.
• Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
• Robin C, Hemery F, Dindorf C, Thillard J, Cabanne L, Redjoul R, Beckerich F, Rodriguez C, Pautas C, Toma A, Maury S, Durand-Zaleski I, Cordonnier C. Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients. BMC Infect Dis. 2017 Dec 5;17(1):747. doi: 10.1186/s12879-017-2854-2.
• Billat PA, Woillard JB, Essig M, Sauvage FL, Picard N, Alain S, Neely M, Marquet P, Saint-Marcoux F. Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity? J Antimicrob Chemother. 2016 Feb;71(2):484-9. doi: 10.1093/jac/dkv342. Epub 2015 Nov 3.
• Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 30, 2020): 400
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2024
• Estimated Primary Completion Date: September 24, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria :

• Candidate (adult) for an allograft of hematopoietic stem cells for which a decision of transplant is made and willing to participate in the cohort.

Exclusion Criteria :

• CMV-seronegative patient receiving a negative CMV donor graft ;
• Patient having signed the consent but not grafted ;
• Patient included in a clinical study on an anti-CMV molecule ;
• Non-insured social patient ;

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sophie ALAIN, Pr; 05.55.05.67.24; sophie.alain@chu-limoges.fr

Contact: Françoise GARNIER-GEOFFROY, CRA; Francoise.GARNIER-GEOFFROY@chu-limoges.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04690933
• Other Study ID Numbers: 87RI18_0011 (NAViRe)
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University Hospital, Limoges
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Limoges
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Pascal TURLURE; Service d'Hématologie Clinique et de Thérapie Cellulaire

• PRS Account: University Hospital, Limoges
• Verification Date: September 2020